Suiyang Tong1, Liangliang Zhang2, Jacob Joseph2, Xuejun Jiang3. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States. 2. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States. 3. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China. Electronic address: xjjiang@whu.edu.cn.
Abstract
BACKGROUND/AIMS: Celastrol pretreatment has been shown to protect against myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism is poorly understood. This study aimed to investigate the cardioprotective effects of celastrol pretreatment on I/R injury and to further explore whether its mechanism of action was associated with the inhibition of high mobility group box 1 protein (HMGB1) expression via the phosphoinositide 3-kinase (PI3K)/Akt pathway. METHODS: In a fixed-dose study, hematoxylin and eosin staining and myocardial enzyme measurements were used to determine the optimal dose of celastrol that elicited the best cardioprotective effects against I/R injury. Furthermore, rats were pretreated with 4 mg/kg celastrol, and infarct size and the levels of myocardial enzymes, apoptosis, inflammatory and oxidative indices, and HMGB1 and p-Akt expression were measured. RESULTS: Our results indicated that celastrol dose-dependently attenuated histopathological changes and the elevation in myocardial enzymes induced by I/R. Moreover, the celastrol pretreatment (4 mg/kg) not only significantly decreased infarct size as well as myocardial enzyme levels but also inhibited myocardial apoptosis, inflammatory response and oxidative stress. Additionally, celastrol downregulated HMGB1 expression and upregulated p-Akt expression in the myocardium. LY294002, a specific pI3k inhibitor, partially reversed the decreased HMGB1 expression, increased p-Akt expression induced by celastrol, and abolished the anti-apoptotic, anti-inflammatory and anti-oxidative effects of celastrol. CONCLUSION: These findings suggest that short-term pretreatment with celastrol protects against myocardial I/R injury by suppressing myocardial apoptosis, inflammatory response and oxidative stress via pI3k/Akt pathway activation and HMGB1 inhibition.
BACKGROUND/AIMS: Celastrol pretreatment has been shown to protect against myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism is poorly understood. This study aimed to investigate the cardioprotective effects of celastrol pretreatment on I/R injury and to further explore whether its mechanism of action was associated with the inhibition of high mobility group box 1 protein (HMGB1) expression via the phosphoinositide 3-kinase (PI3K)/Akt pathway. METHODS: In a fixed-dose study, hematoxylin and eosin staining and myocardial enzyme measurements were used to determine the optimal dose of celastrol that elicited the best cardioprotective effects against I/R injury. Furthermore, rats were pretreated with 4 mg/kg celastrol, and infarct size and the levels of myocardial enzymes, apoptosis, inflammatory and oxidative indices, and HMGB1 and p-Akt expression were measured. RESULTS: Our results indicated that celastrol dose-dependently attenuated histopathological changes and the elevation in myocardial enzymes induced by I/R. Moreover, the celastrol pretreatment (4 mg/kg) not only significantly decreased infarct size as well as myocardial enzyme levels but also inhibited myocardial apoptosis, inflammatory response and oxidative stress. Additionally, celastrol downregulated HMGB1 expression and upregulated p-Akt expression in the myocardium. LY294002, a specific pI3k inhibitor, partially reversed the decreased HMGB1 expression, increased p-Akt expression induced by celastrol, and abolished the anti-apoptotic, anti-inflammatory and anti-oxidative effects of celastrol. CONCLUSION: These findings suggest that short-term pretreatment with celastrol protects against myocardial I/R injury by suppressing myocardial apoptosis, inflammatory response and oxidative stress via pI3k/Akt pathway activation and HMGB1 inhibition.
Authors: Hayder M Al-Kuraishy; Ali I Al-Gareeb; Luay Alkazmi; Ola A Habotta; Gaber El-Saber Batiha Journal: Inflammopharmacology Date: 2022-04-26 Impact factor: 5.093